Buccal and sublingual oral dosage forms are dosage forms that are intended to be held in the mouth or under the tongue until they have completely dissolved. Unlike most oral dosage forms in which the pharmaceutically active ingredient is delivered to the gastrointestinal tract of the patient for absorption of the drug through the stomach or intestinal epithelium, sublingual and/or buccal dosage forms are designed to release the pharmaceutically active ingredient in the mouth for absorption through oral mucosa. Buccal dosage forms are intended to be inserted into the buccal pouch (a space generally defined between a cheek and the gums) and dissolve or erode relatively slowly, whereas sublingual oral dosage forms are intended to be held under the tongue and dissolve more rapidly. As a result, buccal dosage forms, including mucoadhesive formulations, are generally formulated with excipients to optimize drug release into and through oral mucosa and to minimize release of the drug into the gastrointestinal tract. Otherwise, buccal and sublingual dosage forms are substantially similar, the differences being more a matter of degree than of kind.
Sublingual and/or buccal oral dosage forms are preferred for delivering certain pharmaceutically active agents to the bloodstream. For example, many pharmaceutically active agents that are metabolized in the small intestine and/or liver (pharmaceutically active agents exhibiting what is known as “the first pass effect”) can be more effectively administered sublingually or buccally through oral mucosal tissue.
Sublingual and/or buccal oral dosage forms also may provide a faster onset of therapeutic effect and/or improved bioavailability of certain pharmaceutically active agents that can be absorbed through the oral mucosa, thereby bypassing gastrointestinal and hepatic metabolism processes. In addition, such dosage forms may be preferred for administering certain pharmaceutically active agents to achieve better patient acceptance and compliance, especially among those patients that have difficulty swallowing. Buccal and/or sublingual dosage forms may also be employed in some cases to overcome problems with pharmaceutically active agents that are poorly absorbed from the gastrointestinal tract and which may not be effectively administered transdermally, subcutaneously or intravenously.
A known problem with transmucosal administration via buccal and/or sublingual dosage forms is that pharmaceutically active agents, especially those that are not rapidly absorbed through oral mucosa may be washed away in substantial proportion because of the continuous secretion of saliva in the oral cavity. Suitable buccal and/or sublingual dosage forms must remain in contact with oral mucosa for a time sufficient for absorption of a pharmaceutically active agent that is capable of being absorbed through oral mucosa. More specifically, the dosage form must not dissolve and/or disintegrate at such a rapid rate that an undesirably high proportion of the pharmaceutically active ingredient is washed away by saliva into the gastrointestinal tract. However, the rate of disintegration or dissolution of the dosage form must not be so slow as to cause discomfort or inconvenience for the patient, which often leads to non-compliance or poor compliance with a prescribed dosage regimen. Similarly, suitable buccal and/or sublingual dosage forms should be of a size and shape that avoids discomfort to the patient during use, or which leaves a gritty or other undesirable feeling in the mouth.
Cannabinoids include a class of terpenophenoic compounds commonly derived from the cannabis sativa plant, which is commonly known as marijuana. Cannabinoids encompass a variety of compounds structurally related to tetrahydrocannabinol (THC) which can bind to cannabinoid receptors.
Actual or potential therapeutic applications for cannabinoids such as THC include the treatment of multiple sclerosis and other forms of muscular spasm, migraine headache, glaucoma, asthma, inflammation, insomnia, high blood pressure, nausea and vomiting. Other potential therapeutic applications include the use of cannabinoids as oxytoxic, anxiolytic, anticonvulsive, anti-depressive, anti-psychotic, and anti-cancer agents. Cannabinoids have also been used as appetite stimulants.
Oral pharmaceutical dosage forms are generally preferred, relative to other forms, because the oral dosage forms are generally more easily administered, cause less patient discomfort, and achieve greater patient compliance with a prescribed therapeutic regimen. A commercially available product, sold as Marinol® soft gelatin capsules, contains Δ9-tetrahydrocannabinol (THC), also known as dronabinol, as the active ingredient. This product has been approved by the Food and Drug Administration for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation in AIDS patients suffering from wasting syndrome. In the Marinol® dosage form, the active agent is dissolved in sesame oil and encapsulated in a gelatin shell for oral administration. However due to the combined effect of first pass hepatic metabolism, high lipid solubility and low water solubility, only about 10-20% of an administered dose reaches systemic circulation. In addition, there is variability in the maximum or peak concentration of the active agent in the blood plasma between administered dosages. It has also been found that fasting or food deprivation may decrease absorption of THC from the dosage form, and that there is a large inter-subject variability in the amount of THC absorption from the dosage form.
The actual and/or potential utility of cyclodextrin/cannabinoid complexes is recognized in the art. For example, Shoyama (J. Natural Products, 46:5 633-637; Majid, U.S. Pat. No. 5,070,081; Jarho, U.S. Patent Application Publication No. 2005/0153931; Hirayama (Advanced Drug Delivery Review 36 (1998) 125-141; and Watts (WO 99/32107) disclosed the preparation of cyclodextrin/cannabinoid complexes. Watts teaches adding THC to a soluble cyclodextrin in a biphasic oil-water mixture or in water. Majid teaches the formation of agglomerates by adding dissolved THC to a suspension of cyclodextrin and water and hexane. Jarho teaches adding THC and ethanol to cyclodextrin, adding water to dissolve the cyclodextrin, and recovering the precipitate.
Munjal (J. Pharm Sciences 95 11, Nov. 2006) teaches using an antioxidant and a basic pH microenvironment to stabilize THC.